NM_001372.4:c.41_65dupACGCGGATGGGGAACCCGGCGCCGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001372.4(DNAH9):​c.41_65dupACGCGGATGGGGAACCCGGCGCCGA​(p.Asp22GlufsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000549 in 1,347,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

DNAH9
NM_001372.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.576
Variant links:
Genes affected
DNAH9 (HGNC:2953): (dynein axonemal heavy chain 9) This gene encodes the heavy chain subunit of axonemal dynein, a large multi-subunit molecular motor. Axonemal dynein attaches to microtubules and hydrolyzes ATP to mediate the movement of cilia and flagella. The gene expresses at least two transcript variants; additional variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 75 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-11598536-A-AGAACGCGGATGGGGAACCCGGCGCC is Pathogenic according to our data. Variant chr17-11598536-A-AGAACGCGGATGGGGAACCCGGCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 3626282.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH9NM_001372.4 linkc.41_65dupACGCGGATGGGGAACCCGGCGCCGA p.Asp22GlufsTer38 frameshift_variant Exon 1 of 69 ENST00000262442.9 NP_001363.2 Q9NYC9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH9ENST00000262442.9 linkc.41_65dupACGCGGATGGGGAACCCGGCGCCGA p.Asp22GlufsTer38 frameshift_variant Exon 1 of 69 1 NM_001372.4 ENSP00000262442.3 Q9NYC9-1
DNAH9ENST00000579406.1 linkn.68_92dupACGCGGATGGGGAACCCGGCGCCGA non_coding_transcript_exon_variant Exon 1 of 8 1
DNAH9ENST00000454412.6 linkc.41_65dupACGCGGATGGGGAACCCGGCGCCGA p.Asp22GlufsTer38 frameshift_variant Exon 1 of 68 5 ENSP00000414874.2 E7EP17
DNAH9ENST00000579828.5 linkc.41_65dupACGCGGATGGGGAACCCGGCGCCGA p.Asp22GlufsTer38 frameshift_variant Exon 1 of 4 2 ENSP00000463782.1 J3QQK8

Frequencies

GnomAD3 genomes
AF:
0.000130
AC:
19
AN:
146306
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000219
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000681
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000212
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000108
Gnomad OTH
AF:
0.000497
GnomAD4 exome
AF:
0.0000458
AC:
55
AN:
1200714
Hom.:
0
Cov.:
33
AF XY:
0.0000409
AC XY:
24
AN XY:
586518
show subpopulations
Gnomad4 AFR exome
AF:
0.0000806
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000357
Gnomad4 SAS exome
AF:
0.0000514
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000472
Gnomad4 OTH exome
AF:
0.0000603
GnomAD4 genome
AF:
0.000130
AC:
19
AN:
146420
Hom.:
0
Cov.:
32
AF XY:
0.000126
AC XY:
9
AN XY:
71430
show subpopulations
Gnomad4 AFR
AF:
0.000219
Gnomad4 AMR
AF:
0.0000680
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000212
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000108
Gnomad4 OTH
AF:
0.000492
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Nov 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp22Glufs*38) in the DNAH9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH9 are known to be pathogenic (PMID: 30471718). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1230732720; hg19: chr17-11501853; API